Project summary Schizophrenia is a chronic, severe and disabling brain disorder that affects an estimated 1 in 100 persons. Though its key symptoms generally appear late in adolescence, schizophrenia is a neurodevelopmental condition with a strong genetic component and heritability estimated to be as high as 80%. Although therapeutic treatments do exist, they target few putative mechanisms and are not effective in all the patients and/or do not address all the symptoms of the disease. While there have been improvements in the understanding of the biological systems implicated in the pathogenesis and pathophysiology of schizophrenia, progress has been slow and limited both by the difficulty in obtaining relevant tissues from patients and the inadequacy of animal models to deal with the level of genetic complexity involved in this disease. To date, most of the molecular and cellular studies of schizophrenia have been performed on postmortem tissues or on genetically defined mouse models that do not fully recapitulate the human genetic risk or neural phenotype. The rapid advances in induced pluripotent stem cell (iPSC) methodology provide new opportunities to overcome some of the obstacles inherent to the modeling of neurodevelopmental diseases. As a consequence of the groundbreaking work of the Yamanaka laboratory, somatic cells from a simple patient biopsy can be reprogrammed into pluripotent stem cells that can be differentiated into other cell types, including neural cells. Because the resulting neural cells retain that individual's genetic information, this approach has tremendous potential as a tool for understanding genes and pathways that are dysregulated in schizophrenia and can provide a platform for in vitro screening assay for novel therapeutics. The first aim of the project is to apply revolutionary robotic methods to generate pluripotent stem cells from a large cohort of patients and carefully matched controls. We will then use this sample, as well as two existing samples of iPSCs with child onset schizophrenia and/ or known, rare, highly penetrant genetic lesions, to generate excitatory neurons. This will create the first large scale, highly standardized library of iPSC and neurons derived from patients with schizophrenia. The second aim of the project is to perform gene expression profiling on the schizophrenia and control neurons and use innovative systems biological analyses to identify dysregulated pathways in schizophrenia and key molecular drivers that underlie these pathway changes. These key molecular drivers represent potentially high-impact targets for drug development. Altogether, the completion of the aims will provide new insight into the neuronal pathways disrupted in schizophrenia, and identify potential drug targets. The study will also provide the community with a large schizophrenia iPSC cohort and a neuronal RNA sequencing dataset, and will lay the foundation towards establishing a high-throughput platform useful for drug screening and accelerating drug development processes.